Balloon flotation is more important than flow direction in determining the position of flow-directed pulmonary artery catheters.

Pulmonary artery catheters (PAC) inserted using pressure monitoring usually advance into a branch of the right pulmonary artery (PA). However, in some clinical situations it may be desirable to locate the tip of the PAC in a branch of the left PA. A two-part study was undertaken to explore factors that determine the ultimate location of the tip of a PAC. In the clinical study, 33 patients were randomized to supine or right-side down patient positioning during insertion of the PAC. Five patients were excluded because of withdrawal of the PAC during surgery. Seven of 14 PACs inserted in right-side down position were located in a branch of the left PA, while all 14 inserted with the patients supine went to a branch of the right PA (P less than 0.005). This suggests that the effect of upward flotation of the air-filled balloon in the column of blood predominates over movement with the current of maximal blood flow. Using a cardiac bypass pump and a plexiglass model of the pulmonary arterial bifurcation, the effects of lateral positioning on the direction of travel of balloon-tipped catheters were studied. The tip floated upward preferentially, even when flow was obstructed to the upward limb (P less than 0.005). Varying the flow rate in the system between 0.5 and 3.0 L/min and changing the direction of the natural curve of the PAC tip had no impact on this tendency to float upward. The authors conclude that balloon flotation in the column of blood strongly influences PAC tip location, and that this fact can assist in preferentially directing its placement.

Intrathecal oxymetazoline produces analgesia via spinal alpha-adrenoceptors and potentiates spinal morphine.

The intrathecal (i.t.) injection of 100 nmol of oxymetazoline to male, Sprague-Dawley rats significantly increased tail flick latency and paw pressure threshold for 10 h as compared to i.t. saline-treated rats. Oxymetazoline-induced antinociception was accompanied by a 2 degree C decrease in rectal temperature and a delayed but mild sedative effect. Intrathecal phentolamine (50 micrograms), injected 8 h after i.t. oxymetazoline, completely reversed the analgesic and hypothermic effects but did not affect sedation. The intravenous injection of oxymetazoline (100 nmol) had no effect in the paw pressure test and virtually no effect in the tail flick test. Co-injection of i.t. morphine and i.t. oxymetazoline in a molar ratio of 1:28 resulted in significant potentiation of their antinociceptive effects as determined by isobolographic analysis. For i.t. morphine alone, the ED50 and 95% confidence interval (95% CI) was 3.8 nmol (2.8-5.6) in the tail flick test and 7.7 nmol (5.4-12.8) in the paw pressure test. In the combination, the ED50 (95% CI) of i.t. morphine was 0.7 nmol (0.6-0.8) in the tail flick test and 1.2 nmol (1.1-1.4) in the paw pressure test, corresponding to an approximate 6-fold increase in potency. The data indicate that: (1) the antinociceptive and hypothermic effects of i.t. oxymetazoline at 8 h are mediated by spinal alpha-adrenoceptors; (2) peripheral sites, and probably supraspinal sites, do not contribute to i.t. oxymetazoline-induced antinociception [corrected]; and (3) oxymetazoline potentiates the analgesic effects of morphine in the spinal cord of the naive rat.

Tolerance to intrathecal oxymetazoline-induced analgesia, with paradigm-dependent cross-tolerance to intrathecal morphine.

Male, Sprague-Dawley rats, implanted with intrathecal (i.t.) catheters, were given repeated i.t. injections of morphine (40 nmol), oxymetazoline (100 nmol) or saline (10 microliter) at 12-h intervals for 3 days. Antinociception was determined 1 or 1.5 hr after each injection using the tail-flick and paw-pressure tests. Complete tolerance to i.t. morphine and oxymetazoline developed within 72 and 24 hr, respectively. Antinociception after i.t. oxymetazoline (100 nmol) in morphine-tolerant rats, and after i.t. morphine (20 nmol) in oxymetazoline-tolerant rats, was not significantly different from their respective effects in saline-pretreated rats. These data suggest an absence of cross-tolerance between morphine and oxymetazoline in the rat spinal cord. In a separate group of rats, the continuous i.t. infusion of morphine (26 nmol/hr) produced significant antinociception; tolerance to morphine developed within 36 hr. The antinociceptive effect of i.t. oxymetazoline (100 nmol) was significantly attenuated in rats pretreated with continuous i.t. morphine as compared to saline-pretreated rats. In rats pretreated with continuous i.t. oxymetazoline, cross-tolerance to morphine could not be determined due to severe adverse effects during oxymetazoline infusion. The results of this study suggest that functional cross-tolerance between morphine and alpha adrenoceptor agonists in the spinal cord cannot be excluded on the basis of repeated i.t. injection experiments alone.

A study of the interaction between clonidine and morphine on analgesia and blood pressure during continuous intrathecal infusion in the rat.

In the rat, the continuous intrathecal (i.t.) infusion of clonidine (0.4 microgram/hr) significantly increased the tail-flick latency (TF) and the threshold for paw pressure (PP) withdrawal for 5 days and decreased the systolic blood pressure (up to 24 mm Hg) for 7 days. The antinociceptive effect of continuous intrathecal infusion of clonidine (0.4 microgram/hr) in the tail flick and paw pressure tests was not attenuated in rats that were tolerant to morphine. The acute intrathecal administration of clonidine (2.7 micrograms) and morphine (1.0 microgram) resulted in a synergistic interaction in the tail-flick and paw pressure tests. A synergistic interaction was also observed during the continuous intrathecal infusion of morphine (1.25 micrograms/hr) and clonidine (0.2 microgram/hr) in the tail-flick and paw pressure tests. Individually, these doses of morphine and clonidine had no antinociceptive effect. However, intrathecal infusion together yielded peak tail-flick and paw pressure responses comparable to that of 0.4 microgram/hr clonidine alone, without affecting systolic blood pressure. No delay in the onset of tolerance to the analgesic effect was observed with the combination as compared with clonidine (0.4 microgram/hr) alone. The data indicate that clonidine-induced spinal analgesia is independent of endogenous opioid systems linked to mu-receptors in the spinal cord, and that optimization of spinal analgesia (e.g. synergism) can be achieved during continuous intrathecal infusion without affecting cardiovascular activity.

Determination of cross tolerance in rat spinal cord using intrathecal infusion via sequential mini-osmotic pumps.

Continuous intrathecal (IT) infusion via ALZET mini-osmotic pumps was used to induced spinal tolerance to morphine in the rat. Naloxone (1 mg/kg IP), injected on day 3 of continuous IT morphine (10 micrograms/hr), produced mild withdrawal symptoms in all morphine-treated animals. In rats pretreated with continuous IT morphine (10 micrograms/hr) or saline, systemic morphine (2, 4, 8, 10 and 15 mg/kg IP) produced equivalent, dose-dependent antinociception using the tail-flick and paw pressure tests. The rostral and caudal distribution of methylene blue dye in rat spinal cord was determined on days 1-7 of continuous IT infusion. The dye remained localized near the catheter tip throughout infusion; maximum distribution was 1.5 cm rostrally and 1.0 cm caudally. The data indicate that morphine, infused at the rate of 10 micrograms/hr, does not undergo extensive redistribution in the spinal cord. A sequential, double mini-osmotic pump technique for cross tolerance studies in rat spinal cord is described. In rats pretreated with continuous IT norepinephrine for 4 days, the antinociceptive actions of continuous IT morphine were reduced but not significantly different from saline-pretreated animals. These data suggest that morphine, injected into the spinal cord, does not produce behavioural analgesia by activation of local adrenergic systems.

Arterial isoflurane concentration and EEG burst suppression during cardiopulmonary bypass.

Isoflurane (1.5 to 3.0 vol% in oxygen) was used to control intraoperative hypertension in 10 patients undergoing hypothermic cardiopulmonary bypass surgery. Isoflurane was administered through the membrane oxygenator of the bypass pump and yielded plateau concentrations in arterial blood ranging from 36.6 to 84.4 micrograms/ml (0.5 and 1.16 vol%, respectively). Isoflurane dosing resulted in prolonged periods (21 to 63 minutes) of EEG burst suppression and isoelectric activity in nine patients. Burst suppression was not a result of hypothermia. There was a close temporal relationship between isoflurane concentration and the onset of burst suppression (mean onset time: 27.3 +/- 4.56 minutes after isoflurane begun). The mean arterial isoflurane concentration at the onset of burst suppression was 46.5 +/- 10.7 micrograms/ml; the nasopharyngeal temperature was 26.0 degrees +/- 0.61 degrees C. Isoflurane was eliminated rapidly from blood with a mean apparent t1/2 of 18.8 +/- 5.46 minutes.

Transducer offset by electrocautery resulting in erroneous blood pressure measurement.

During a coronary artery bypass operation arterial blood pressure measured with a Bentley Trantec model 800 transducer increased erroneously while continuous electrocautery was being used. This phenomenon has recurred infrequently, with fictitious hypotension being observed in one patient. To reproduce the problem of pressure offset during electrosurgery a bench test demonstrated that with peak to peak voltage of 20 volts from the electrosurgical unit, three of seven Bentley transducers had offsets as much as +/- 50 mmHg. It is important for anaesthetists to determine if electrosurgery units are functioning before treating apparent pressure drifts.

Analgesia and autonomic function following intrathecal administration of morphine and norepinephrine to the rat.

The acute intrathecal (i.t.) administration of 10, 25, 50, and 100 microgram morphine and 7.5, 10, 15, and 30 microgram (-)norepinephrine (NE) to the rat produced dose-dependent, long-lasting analgesia as assessed by the tail-flick and hot-plate tests. For i.t. morphine, maximum analgesia was observed 30-60 min after drug administration. The duration of analgesia in the tail-flick test ranged from 30 to 150 min; the duration of analgesia in the hot-plate test ranged from 60 to 120 min. For i.t. NE, maximum analgesia was observed 15-60 min after drug infusion. The duration of NE-induced analgesia in the hot-plate test ranged from 45 to 120 min and was 120 min in the tail-flick test. The effects of acute i.t. and intravenous (i.v.) infusions of morphine (10 microgram) and NE (15 microgram) on heart rate, blood pressure, arterial pH, partial pressure of oxygen (Po2), partial pressure of carbon dioxide (Pco2), and standard bicarbonate were determined over 45 min in rats anesthetized with alpha-chloralose (70 mg/kg). Morphine significantly decreased Po2 throughout the experiment but did not affect blood pressure, heart rate, pH, Pco2 and standard bicarbonate. A significant increase in blood pressure (137% of control) was observed 2.5 min after i.t. administration of NE. Intravenous NE produced a marked increase in blood pressure (246% of control) followed by a compensatory decrease in heart rate. There were no significant changes in blood gases with i.t. and i.v. NE. The data suggest that i.t. morphine and NE can produce effective analgesia with minimal effects on cardiovascular and respiratory function.

Intrathecal clonidine: analgesia and effect on opiate withdrawal in the rat.

Clonidine, an alpha 2 adrenergic agonist, has analgesic properties and recently has been used to suppress opiate withdrawal. These two properties theoretically make it a suitable analgesic substitute in patients tolerant to opioids. The objectives of this study were to see if intrathecal clonidine is analgesic and whether it can modify morphine withdrawal at the spinal level. Rats chronically implanted with catheters in the lumbar subarachnoid space were utilized. In analgesia experiments, intrathecal clonidine produced analgesia with the peak effect in the paw-lick test occurring at 200nM, and in the tail-flick test analgesia was apparent at 100 nM and peaked at 400 nM (in 10 microL Ringer's lactate). In dependency experiments, animals dependent on morphine (300 mg X kg-1) received intrathecal clonidine 25, 50, 200 nM in 10 microliter Ringer's lactate 72 h after morphine. Following this, a naloxone challenge, 3 mg X kg-1 was administered and withdrawal assessed. Clonidine-treated animals showed significant weight loss and decrease in temperature, and those treated with high doses showed marked hypothermia and hind-limb flaccidity. Intrathecal clonidine prevented the hyperalgesia associated with opiate withdrawal but did not affect the occurrence of the majority of behavioral signs (e.g., piloerection, irritability) associated with morphine withdrawal. Intrathecal clonidine prevented the naloxone-induced increase in blood pressure during withdrawal and in animals not treated with morphine-produced hypotension. Thus, intrathecal clonidine is analgesic, and part of the antiwithdrawal action of clonidine may be exerted at the spinal level.

Effects of naloxone on exercise performance.

This study was designed to investigate the effects of naloxone on athletic performance in humans. Two groups of elite middle-distance runners performed a maximal or a submaximal exercise protocol following the double-blind intravenous injection of either naloxone (0.15 mg X kg body wt-1) or saline. The maximal test (group M) was comprised of a short-duration treadmill run to maximal intensity; the submaximal test (group S), a prolonged submaximal treadmill run to exhaustion. O2 uptake, heart rate, ventilation, and perceived exertion were determined during each test. Perception of pain was assessed after exercise by use of a modified McGill pain questionnaire. No significant differences between placebo and naloxone treatments were found in any of the measured variables at the usually accepted 5% (P = 0.05) confidence level; however, evidence suggesting differences (i.e., P = 0.1 to 0.05) in these important respects was observed. In group M, maximal exercise performance measured by maximal O2 consumption was not different between placebo and naloxone; results suggest that VE was increased (P = 0.08) following naloxone, but only at the final work stage. In group S, exercise performance time was reduced following naloxone (P = 0.09), whereas the affective component of pain was increased (P = 0.06); no differences in the measured physiological variables were observed. These results suggest the following: 1) the opiate receptor-endorphin system may alter the perception of pain associated with prolonged high-intensity submaximal exercise with a resultant significant effect on performance; and 2) it may play a role in the control of ventilation during maximal exercise.

Thiopental bolus during carotid endarterectomy-rational drug therapy?

Ten studies were performed to examine the time course of arterial and venous thiopental concentrations following the administration of thiopental (4 mg X kg-1 over 3 min) for cerebral protection during carotid occlusion in nine patients undergoing elective carotid endarterectomy; in five patients the time course of EEG change was also studied. The arterial and venous thiopental concentrations were similar with no evidence of a sustained arterial-venous gradient. The average arterial concentration was 20.1 microgram X ml-1 +/- 10 (SD) at 2 min after thiopental, and fell rapidly to 13.0 micrograms X ml-1 +/- 3.2 at 5 min, 10.7 micrograms X ml-1 +/- 4.4 at 10 min and 6.2 micrograms X ml-1 at 30 min. After thiopental the EEG record showed an increase in delta activity and in four patients a burst suppression pattern was seen. The duration of burst suppression activity was variable (130 to 367 seconds) but in all instances cortical activity had returned to the pre-thiopental level by five to ten minutes. Thus concentrations of thiopental of 10-30 micrograms X ml-1 were associated with EEG burst suppression and both were seen only within the first five minutes after drug administration. In contrast the carotid artery was occluded for considerably longer (26 +/- 4) minutes. We conclude that, since there was no sustained arterial-venous gradient, either arterial or venous concentrations are adequate for the study of thiopental pharmacokinetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Massive endobronchial hemorrhage during cardiopulmonary bypass: treatable complication of balloon-tipped catheter damage to the pulmonary artery.

Massive endobronchial hemorrhage due to balloon-tipped catheter rupture of a branch of the pulmonary artery in a fully heparinized patient undergoing cardiopulmonary bypass is potentially lethal. Death occurs due to asphyxiation. Endobronchial intubation (double-lumen endotracheal tube) appears to be a simple and effective method for control of the airway and tamponade of the bleeding site, which allows for completion of the surgical procedure until protamine sulphate reversal can be achieved.

Physical dependence on nitrous oxide in mice: resemblance to alcohol but not to opiate withdrawal.

Mice of two strains, Crl:CD-1(1CR)Br and C57BL6, were exposed to nitrous oxide at concentrations of 50, 65 and 80 per cent for 34 or 68 hours. Cessation of nitrous oxide resulted in characteristic convulsions similar to those seen in alcohol withdrawal in all mice. These peaked in severity within 2-3 minutes after removal from nitrous oxide and declined over 6 hours. The severity and duration of these convulsions were related to the nitrous oxide concentration and duration of exposure. Naloxone or naltrexone produced no significant increase in severity of convulsions. The narcotic antagonists did not precipitate acute weight loss or characteristic jumping behaviour seen in animals dependent on opiates. These results demonstrate that chronic exposure to nitrous oxide results in development of physical dependence which resembles alcohol and not opiate dependence. Analgesia and physical dependence produced by nitrous oxide appear to be mediated through separate mechanisms.

Effects of halothane on the pharmacokinetics of lidocaine in digitalis-toxic dogs.

Following the production of digitalis toxicity in dogs as manifested by ventricular tachycardia, the pharmacokinetics of lidocaine treatment of the arrhythmia were determined during pentobarbitone anaesthesia and pentobarbitone-halothane anaesthesia. The elimination rate constants, beta and Ke, and the biological half life T1/2beta were statistically significantly increased during halothane anaesthesia. The volume of distribution was unchanged. The results indicate that the therapeutic loading dose of lidocaine need not be altered during halothane anaesthesia but if a constant infusion is used, the rate of infusion would have to be decreased four fold to avoid toxic plasma levels of lidocaine.

Prolongation of anesthetic action by BNPP (bis-[p-nitrophenyl] phosphate).

Bis-[p-nitrophenyl] phosphate, BNPP, an enzyme inhibitor of the organophosphate class, has been used to inhibit the enzyme, carboxylic ester hydrolase EC 3.1.1.1. Esterases play a major role in the rapid metabolism of propanidid in vivo; in fact, the short duration of action of this intravenous anesthetic agent is due to this rapid hydrolysis. The duration of anesthesia with propanidid alone in healthy mongrel dogs was 10.1 +/- 2.1 (SEM) minutes. When the dogs were pretreated with BNPP, propanidid anesthesia time was prolonged to 38.2 +/- 7.9 (SEM) minutes. Measurements of serum propanidid concentration demonstrated that prolonged high levels of propanidid were associated with the extended anesthesia time. Therefore, BNPP can significantly alter the anesthetic action of propanidid by inhibition of the enzyme system responsible for the rapid hydrolysis of the agent. The experimental model used in the present study provides a means for investigation of effects of certain drugs when their metabolism is impaired.